SOHO State of the Art Updates and Next Questions: Waldenström Macroglobulinemia - 2021 Update on Management and Future Directions

Waldenstrom macroglobulinemia (WM) is a low-grade B-cell lymphoproliferative disorder. It is defined by having ≥ 10% bone marrow infiltration with lymphoplasmacytic cells and/or an immunoglobulin M (IgM) monoclonal gammopathy of ≥3g/dL. Risk factors include a personal history of IgM MGUS, and a family history of WM or a related disorder. Race, sex, and chronic antigen stimulation also appear to influence risk. Between 93 to 97% of patients with WM have a somatic mutation of the MYD88 gene. Of these, approximately 30% also have a mutation of CXCR4. The presence of a MYD88 mutation is associated with higher 10-year overall survival (90% vs. 73%; P < .001), while CXCR4 mutation status does not appear to have a similar effect. Based on consensus guidelines, WM patients with a disease-related hemoglobin level of less than 10g/dL, a platelet count of less than 100×10 9/L, bulky adenopathy or organomegaly, symptomatic hyperviscosity, severe neuropathy, amyloidosis, cryoglobulinemia, cold agglutinin disease, or evidence of disease transformation, should be considered for immediate therapy. Patients not meeting these criteria may be observed, with monitoring at 3 to 6 month intervals. When treatment is warranted, combinations of rituximab with alkylating agents and proteasome inhibitors are often effective, as are Bruton's tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors. Selection among available regimens should take patients' gene mutation profile, disease-related features, and co-morbid conditions into account. Promising novel therapies in development include non-covalent BTK inhibitors, CXCR4 antagonists, BCL 2 inhibitors, bi-specific antibodies, radioimmunoconjugates, and CD19- and CD20-Targeted Chimeric Antigen Receptor T cells.